module 2 tuts p7

ADVERSE DRUG REACTIONS

a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man

ADVERSE DRUG REACTIONS

Examples:

• Propranolol

  • Blocks Beta 1 receptors → normalize blood pressure (intended effect)

  • Blocks Beta 2 receptors → bronchoconstriction (noxious effect)

• Morphine

  • Narcotic analgesic → affect CNS

  • Therapeutic dose 15–30 mg q4h → rashes, constipation

  • More than the therapeutic dose → Signs and symptoms of toxicity:

    • Coma

    • Pinpoint pupils

    • Respiratory depression

Propranolol

• Nonselective BB

• Blocks Beta 1 receptors → normalize blood pressure (intended effect)

• Blocks Beta 2 receptors → bronchoconstriction (noxious effect)

Selective Beta Blocker

Block beta 1 receptor only - can be used for px with asthma: Ate BiBe Met Esmo Nebi

• Atenolol

• Bisoprolol

• Betaxolol

• Metoprolol

• Esmolol

• Nebivolol

Morphine

• Narcotic analgesic → affect CNS

• Therapeutic dose 15–30 mg q4h → rashes, constipation

• More than the therapeutic dose → Signs and symptoms of toxicity:

  • Coma

  • Pinpoint pupils (miotic)

  • Respiratory depression

Naloxone / Naltrexone

Antidote for opioid toxicity:

• Naloxone - Narcan®

• Naltrexone - Trexan®

  • From 5 cycle/min → 12 to 20 cycle/min RR

  • Pupils is responding (dilating)

  • No comatose

ADVERSE DRUG REACTIONS

• Augmented

• Bizarre

• Continuous

• Delayed

• End of Use

• Failure of Efficacy

AUGMENTED ADR

• Most common (75% of reported cases)

• Related to the pharmacologic action of the drug

• Predictable

• Preventable

• Dose-dependent - ↑ dose = ↑ severity

• AVOID → lower the dose

AUGMENTED ADR

Dose dependent

• Oral Hypoglycemic Agents like Sulfonylureas

  • Insulin secretagogues = increase secretion of insulin = normal blood sugar levels

  • If extended, lower than normal = hypoglycemia

• Prevent:

  • Recommend lowest possible dose

  • Recommend a decrease in the dose of the drug

AUGMENTED ADR

2 TYPES:

• Extension Effects

• Side Effects

Extension Effects

• Anti hypertension → hypotension

• OHAs → hypoglycemia

• Serotonin Syndrome caused by SSRIs (Selective Serotonin Reuptake Inhibitors)

  • Fever

  • Agitation

  • Sweating (profused)

  • Tremors

• Patient Fall caused by CNS depressants (Zolpidem, Olanzapine, Diphenhydramine)

Serotonin Syndrome

• Caused by SSRIs (Selective Serotonin Reuptake Inhibitors) like FLUOXETINE

• Symptoms:

  • Fever

  • Agitation

  • Sweating (profused)

  • Tremors

CNS depressants

• Patient Fall caused by _____ (Zolpidem, Olanzapine, Diphenhydramine)

  • Z drugs: Zolpidem, Zaleplon, EsZopiclone

  • Anti-psychotic drug: Olanzapine

  • 1st Gen Antihistamine: Diphenhydramine (non polar → cross BBB)

• Extension effect: Can cause dizziness and drowsiness

2nd Generation Antihistamine

Recommended antihistamine for people who will drive heavy machinery, drive a car, pilot flying a plane

• Loratadine: Non sedating - polar - cannot cross BBB

Side Effects

• Dry cough: ACE inhibitors due to accumulation of bradykinin

  • Alternative: ARBs (Losartan, Valsartan)

• Endocrine side effects → Cimetidine (gynecomastia)

• Kernicterus → Sulfonamides in neonates (bilirubin displacement)

• Cholestatic Hepatitis → Erythromycin estolate

• Lactic acidosis → Metformin

ACE inhibitors

• Dry cough: ____ due to accumulation of bradykinin

  • Side effect: Inhibit the conversion of bradykinin to kinin leading to its accumulation → dry cough

  • Alternative: ARBs (Losartan, Valsartan)

• Main effect: Decrease BP by inhibiting the enzyme that converts Angiotensin I to Angiotensin II (-prils)

Cimetidine

• Anti-androgenic effects / Endocrine side effects → ____ (gynecomastia)

• Main effect: Histamine 2 receptor blocker for PUD

• Side effect: When H2 receptors are blocked → increase prolactin levels = gynecomastia

  • Alternative: Ranitidine (rarely causing gynecomastia in male px)

Sulfonamides

• Kernicterus → ____ in neonates (bilirubin displacement)

  • Protein displacement: Bilirubin molecules are bound to albumin → if given with ____ like SULFISOXAZOLE, they will be displacing bilirubin from albumin bc they have more affinity to it

  • Bilirubin leaks to the brain of neonates → brain damage (kernicterus)

• Main effect: antibacterial agent

Erythromycin estolate

• Cholestatic Hepatitis → ____

• Main effect: Antibacterial agent

• Side effect: Block the flow of bile → problems in liver

  • Severe abdominal pain

  • Jaundice - yellow skin, yellow eyes

Lactic acidosis

• Caused by the drug METFORMIN

• Main effect: Oral Hypoglycemic Agent

• Side effect: Can cause an increase in lactic acid levels in the blood → accumulation = acidosis

BIZARRE ADR

• Least common / rare

• Not related to the pharmacologic action

• Not Preventable

• Not Predictable

• Not Dose Dependent

Bizarre ADR

2 TYPES:

• Idiosyncratic Reactions

• Hypersensitivity / Allergic reactions (exaggerated immune response to normal dose)

Idiosyncratic Reactions

• Rare but very severe genetically determined ADR

• Example: Stevens-Johnson Syndrome caused by

  • Carbamazepine

  • Phenytoin

  • Sulfonamides

  • NSAIDs

• Gene: HLA-B 15:02

True

• Idiopathic → unknown

• Idiosyncratic → genetically determined

Stevens-Johnson Syndrome

• Caused by

  • Carbamazepine

  • Phenytoin

  • Sulfonamides

  • NSAIDs

• Gene: HLA-B 15:02

• Symptoms:

  • Fever

  • Blistering of the skin

  • Skin peeling

Hypersensitivity / Allergic reactions

Exaggerated immune response to normal dose

• Example: Penicillins and Cephalosporins → anaphylaxis

Penicillins and Cephalosporins

They are haptens

• Small molecules (>10,000 daltons)

• Not immunogenic

• If binded to large molecules like albumin = they become immunogenic = OA or exaggerated rxns

• Lead to ANAPHYLACTIC REACTION

  • BRONCHOCONSTRICTION - cannot breathe properly

  • VASODILATION - hypotension

  • FATAL

Epinephrine

DOC for anaphylaxis

• Bronchodilator

• Vasoconstrictor

Hypersensitivity reactions

• Type I - Immediate or Anaphylactic

• Type II - Cytotoxic

• Type III - Immune Complex

• Type IV - Delayed or Cell-Mediated

Type I Hypersensitivity

• Immediate or Anaphylactic

• Mediator: IgE

• Onset: With in mins

• Example: Allergies, Anaphylaxis caused by haptens

Type II Hypersensitivity

• Cytotoxic, toxic to red blood cells

• Mediator: IgG/IgM

• Onset: Hours to Days

• Example:

  • Blood Dyscrasia (Aplastic Anemia = Chloramphenicol)

    • Aplastic Anemia is the most severe type of anemia

  • Autoimmune Hemolytic Anemia = Methyldopa

    • Break down of RBC

Type III Hypersensitivity

• Immune Complex (Antigen-antibody complex)

• Mediator: IgG/IgM

• Onset: Hours - Days

• Example:

  • Serum Sickness (same with allergy but more on biologicals)

  • Systemic Lupus Erythematosus like symptoms (ex. drugs that are metabolized by acetylation → HIPS)

Systemic Lupus Erythematosus like symptoms

Immune complex hypersensitivity; Examples are drugs that are metabolized by acetylation → HIPS

• Hydralazine

• Isoniazid

• Procainamide

• Sulfonamides (sulfasalazine)

Type IV Hypersensitivity

• Delayed or Cell-Mediated

  • Need antigen presentation (72 hrs)

• Mediator: T Cells

• Onset: Days

• Example:

  • Contact Dermatitis - UROSHIOL (Poison Ivy - rhus radicans)

  • Mantoux Reaction - Tuberculin Test

CONTINUOUS ADR

• LONG TERM, DOSE- and TIME-related

  • Addiction

  • Dependence

  • Tolerance

  • Tachyphylaxis

  • Cushing Syndrome (from long-term steroids)

Addiction

• Patient takes the drug compulsively despite potential harm

• Example: Methamphetamine / Shabu, Ecstasy

Ecstasy

CHEMICAL NAME: 3, 4-methylenedioxy methamphetamine (MDMA)

THC from Marijuana

CHEMICAL NAME: LEVOROTATORY TRANS-DELTA-9-TETRAHYDROCANNABINOL

Dependence

• Physical dependence:

  • Without the drug, affected the activities of daily living

• Psychological dependence:

  • Without the drug, px can't think well

• Abrupt discontinuation of the drug may lead to withdrawal

• Example: Diazepam

  • Abrupt d/c may lead to INSOMNIA

Dependence

Management:

1. Tapering the dose of the drug (10mg, 7.5mg, 5mg, 2.5mg, 0)

2. Medication switching (not causing dependence)

3. Medication augmentation (+ another drug)

   • Give carbamazepine while tapering the dose of benzodiazepines

Tolerance

• Diminished effect at a normal dose

• Example: Nitroglycerin → patches must be removed after 12 hours to prevent tolerance

  • Bringing back the sensitivity of the patient to the drug to prevent diminished effects of the drug

DELAYED ADR

• Time dependent

• Teratogenicity

• Carcinogenicity

TERATOGENICITY

• Ability of any agent to cause fetal harm (affect developing fetus)

Teratogenicity

Example:

• Carbamazepine / Valproic Acid

  • Anticonvulsants

  • Affect the metabolism of folic acid → Leads to Neural Tube Defects (Spina Bifida)

• Thalidomide

  • Used to treat hyperemesis gravidarum (severe morning sickness)

  • Can cause PHOCOMELIA (underdeveloped limbs)

Carbamazepine / Valproic Acid

• Anticonvulsants

• Affect the metabolism of folic acid → Leads to Neural Tube Defects (Spina Bifida)

Neural Tube Defects

3 types: (happens due to did not take folic acid while pregnant, or took Carbamazepine & Valproic Acid while pregnant)

• Spina bifida

• Encephalocele

• Anencephaly

Anticonvulsants for Pregnant Women

Safe anticonvulsants for pregnant women

• Lamotrigine

• Levetiracetam

• Gabapentin

Thalidomide

• Used to treat hyperemesis gravidarum (severe morning sickness)

• Can cause PHOCOMELIA (underdeveloped limbs)

• It is now used as anti-leprosy (but still CI for pregnant women)

Carcinogenicity

To cause cancers

• Examples: Asbestos, Benzopyrene, Benzene

• Asbestos

  • Chemically magnesium silicate

  • When inhaled may cause silicosis leading to lung cancer

  • Additional: Talc is also magnesium silicate

• Benzopyrene

  • Cigarette smoke = lung cancer

• Benzene

  • Acute myeloid leukemia

Asbestos

Chemically magnesium silicate

• When inhaled may cause silicosis leading to lung cancer

• Additional: Talc is also magnesium silicate

Benzopyrene

Cigarette smoke = lung cancer

Benzene

• Acute myeloid leukemia

END OF USE ADR

• Withdrawal Effects

Withdrawal Effects

• Abrupt discontinuation of steroids → Adrenal insufficiency

• Abrupt discontinuation of clonidine → Rebound hypertension

• Remedy → tapering the dose

Adrenal insufficiency

• Abrupt discontinuation of steroids

Rebound hypertension

• Abrupt discontinuation of clonidine

Rebound congestion

• Abrupt discontinuation of nasal decongestants → ___ (Rhinitis medicamentosa)

• To classify this is actually an augmented ADR ; extension effect

• Not withdrawal effect

• Prolonged kasi ang paggamit ng nasal decongestant → mas nagbabara pa lalo

FAILURE OF EFFICACY ADR

Fails to elicit its supposed pharmacologic effect

FAILURE OF EFFICACY ADR

Causes:

• Wrong Route of Administration

• Antagonistic Drug Interactions

• Patient non-compliance

• Anti-microbial resistance

Wrong Route of Administration

Example:

• Potassium supplements → must not be administered by rapid IV push / IV Bolus (Hyperkalemia → dangerous, causes arrhythmias, cardiac arrest)

Antagonistic Drug Interactions

Ex:

• Warfarin + green leafy vegetables (vit K)

Patient non-compliance

• Patient is not compliant → fail to elicit supposed pharmacologic effect

Anti-microbial resistance

• AMR

• Causative agent is resistant to the antimicrobial agent → treatment failure

• Ex. Staphylococcus aureus

  • Treated with the drug penicillin but became resistant

  • PRSA - Penicillin Resistant S. aureus → METHICILLIN (misused & abused)

  • MRSA - Methicillin Resistant S. aureus → VANCOMYCIN

  • VRSA - Vancomycin Resistant S. aureus → LINEZOLID

METHICILLIN

• PRSA - Penicillin Resistant S. aureus →

VANCOMYCIN

• MRSA - Methicillin Resistant S. aureus →

LINEZOLID

• VRSA - Vancomycin Resistant S. aureus →

B. Non-selective beta blocker (like Propranolol)

Which of the following drug may aggravate asthma?
A. Protease inhibitor
B. Non-selective beta blocker
C. Calcium channel blocker
D. ACE inhibitor

A. Estolate

A reversible cholestatic hepatitis with fever and jaundice has been observed as an adverse reaction in patients taking Erythromycin ________________.
A. Estolate
B. Base
C. Ethylsuccinate
D. Stearate

C. Cimetidine

Which of the following medications is most likely to cause drug interaction and endocrine side effects?
A. Ranitidine
B. Omeprazole
C. Cimetidine
D. Lansoprazole

B. I and III

Which of the following medications can increase the likelihood of patient fall?
I. Zolpidem
II. Loratadine
III. Olanzapine

A. I, II and III
B. I and III
C. II and III
D. I and II

B. Augmented

What type of adverse reaction is exemplified by Serotonin Syndrome due to the administration of an SSRI?
A. Therapeutic Failure
B. Augmented
C. Teratogenic
D. Bizarre

C. Rhabdomyolysis (myalgia, myasthenia)

What adverse effect may result from the intake of HMG-CoA Reductase Inhibitors?
A. Bleeding
B. Hypoglycemia
C. Rhabdomyolysis
D. Hypertensive Crisis

D. Sulfisoxazole

Which of the following may cause drug-induced kernicterus in neonates?
A. Doxycycline - tetracycline (yellow teeth)
B. Chloramphenicol - gray baby syndrome
C. Isoniazid
D. Sulfisoxazole

C. IV bolus

Which of the following is NOT an advisable mode of administration for potassium supplements?
A. Modified release tablet, po
B. Oral Solution
C. IV bolus
D. IV infusion

A. Hyperkalemia

Which of the following is a side effect of Digoxin?
A. Hyperkalemia - blocks ATPase pump (PiSo)
B. Hypokalemia
C. Hypernatremia
D. Hyponatremia

MONITORING PARAMETERS (LABORATORY TESTS)

✔ Monitor safety and effectiveness of a drug

✔ Examples:

• Isoniazid - Anti-TB; Hepatotoxic (liver damage)

  • Laboratory parameter: ALT (Alanine amino Transferase), AST (Aspartate amino Transferase

• Febuxostat - For gout or hyperuricemia

  • Efficacy - decreased uric acid in the blood

Liver enzymes

• ALT (Alanine amino Transferase)

  • SGPT

  • Serum Glutamic Pyruvic Transaminase

• AST (Aspartate amino Transferase

  • SGOT

  • Serum Glutamic Oxaloacetic Transaminase

  • ASTig ang SGOT niya

MONITORING PARAMETERS (LABORATORY TESTS)

• False Positive

• False Negative

False Positive

A test which incorrectly indicates that a particular condition or attribute is present

False Positive

Example:

• Red urine is interpreted as blood in urine in a patient taking Rifampicin

• Rifamipicin is an RNA synthesis inhibitor

• May be interpreted as:

  • Hematuria/blood in urine (organoleptic evaluation)

False Negative

A test which incorrectly indicates that a particular condition or attribute is absent

False Negative

Example:

1. The test indicates a normal blood sugar level in patients with untreated Diabetes Mellitus

2. The test does not detect the virus from an infected person

TESTS AND PROCEDURES

• PT INR

• aPTT

• Creatine Kinase MB (CK-MB)

• Troponin I

• Creatinine Clearance

• Serum Creatinine

• ECG

• EEG

• PEFR

• Endoscopy

PT INR

• Prothrombin Time - International Normalized Ratio

  • Prothrombin Time is the time it takes for the blood to clot

• Plasma + Calcium + Tissue Thromboplastin = activate extrinsic coagulation pathway

• Screens the Extrinsic Coagulation Pathway

• Monitoring Parameter for WARFARIN Therapy

aPTT

• Activated Partial Thromboplastin Time

• Remove platelets in the plasma → PPP (Platelet Poor Plasma)

• PPP + Activator (silica or kaolin) + Phospholipids = Incubated + Calcium ions

• Screens the Intrinsic Coagulation Pathway

• Monitoring Parameter for HEPARIN Therapy

• Normal aPTT = 25 to 35 seconds

Creatine Kinase MB (CK-MB)

• Muscle damage such as in acute myocardial infarction

• Other isoenzymes: CK-MM (skeletal muscle), CK-BB (brain)

Troponin I

• Contractile protein

• Present in heart

• Muscle damage such as in acute myocardial infarction

Creatinine Clearance

• Volume of blood cleared of creatinine per minute

• Unit: mL/min

• If decreased = decreased renal function → kidney failure

• Factors:

  • A - Age (years)

  • B - Body Weight (kg)

  • C - Serum Creatinine (mg/dL)

B. 45.61 mL/min

The serum creatinine of a 55-year old female patient, weighing 150 lb, was 1.5 mg/dL. What is her creatinine clearance?

A. 52.65 mL/min

B. 45.61 mL/min

C. 40.2 mL/min

D. 27.3 mL/min

---

CrCl = (140-A) (B) / (C × 72) × 0.85 (female)

• A = 55 years old

• B = 150lb ÷ 2.2 = 68.1818kg

• C = 1.5mg/dL

• Female = × 0.85

• (140-55) (68.1818) / (1.5 × 72) × 0.85

• 5795.453 / 108 = 53.6616 × 0.85

• 45.61 mL/min

  • Normal CrCl for females is 90 to 110 mL/min

  • Px CrCl below normal = decreased renal function

Serum Creatinine

• SCr

• Produced during skeletal muscle contraction

• Excreted by the kidneys

• mg/dL

• Its level in the blood increases when renal function diminishes

• ↑SCr = kidney failure

ECG

• Electrocardiogram

• To record heart’s electrical signals

EEG

• Electroencephalogram

• To record brain’s electrical signals

PEFR

• Peak Expiratory Flow Rate

• Volume of air expelled by the lungs in one quick exhalation = measured using SPIROMETER

• A process to assess lung function and diagnose pulmonary diseases

• If decreased ang PEFR:

  1. Impaired lung function

  2. Obstruction in the respiratory tract

Endoscopy

A procedure in which an instrument is introduced into the GI tract to diagnose diseases like colon cancer

BIOLOGICAL MARKERS

• Proteins, peptides produced by abnormal cells (objective indications of medical states)

  • Cystatin C

  • PSA (Prostate Specific Antigen)

  • CEA (Carcinoembryonic Antigen)

  • AFP (Alpha-Fetoprotein)

A. INR

Which of the following is important in monitoring the effects of Warfarin?

A. INR

B. Hemoglobin A1C - blood glucose

C. Platelet count - in cases of thrombocytopenia (↓ platelet counts)

D. AST:ALT ratio - liver function

A. Creatine Kinase-MB

Which of the following are cardiac biomarkers released when muscle cells are damaged during acute myocardial infarction?

A. Creatine Kinase-MB

B. Lactate Dehydrogenase

C. Creatinine

D. Neutrphil

A. False negative result

A new test for HIV does not detect the presence of the virus in someone who is infected. This is known as a ________________.

A. False negative result

B. True negative result

C. False positive result

D. True positive result

B. Renal

Cystatin C is a biomarker in ______________ disease.

A. Pulmonary

B. Renal

C. Hepatic

D. Cardiac

B. I and II

Which of the following statements are true regarding creatinine? (SCr)

I. It is produced during skeletal muscle contraction ✓

II. It is excreted by the kidneys ✓

III. Its level in the blood decreases if the renal function diminishes (increase)

A. I and III

B. I and II

C. I, II and III

D. II and III